Exploiting the synergy between carboplatin and ABT-737 in the treatment of ovarian carcinomas

Platinum drug-resistance in ovarian cancers is a major factor contributing to chemotherapeutic resistance of recurrent disease. Members of the Bcl-2 family such as the anti-apoptotic protein Bcl-XL have been shown to play a role in this resistance. Consequently, concurrent inhibition of Bcl-XL in combination with standard chemotherapy may improve treatment outcomes for ovarian cancer patients. Here, we develop a mathematical model to investigate the potential of combination therapy with ABT-737, a small molecule inhibitor of Bcl-XL, and carboplatin, a platinum-based drug, on a simulated tumor xenograft. The model is calibrated against in vivo\ud experimental data, wherein tumor xenografts were established in mice and treated with ABT-737 and carboplatin on a fixed periodic schedule, alone or in combination, and tumor sizes recorded regularly. We show that the validated model can be used to predict the minimum drug load that will achieve a predetermined level of tumor growth inhibition, thereby maximizing the synergy between the two drugs. Our simulations suggest that the time of infusion of each carboplatin dose is a critical parameter, with an 8-hour infusion of carboplatin administered each week combined with a daily bolus dose of ABT-737 predicted to minimize residual disease. We also investigate the potential of ABT-737 co-therapy with carboplatin to prevent or delay the onset of carboplatin-resistance under two scenarios. When resistance is acquired as a result of aberrant DNA-damage repair in cells treated with carboplatin, the model is used to identify drug delivery schedules that induce tumor remission with even low doses of combination therapy. When resistance is intrinsic, due to a pre-existing cohort of resistant cells, tumor remission is no longer feasible, but our model can be used to identify dosing strategies that extend disease-free survival periods. These results underscore the potential of our model to accelerate the development of novel therapeutics such as ABT-737, by predicting optimal treatment strategies when these drugs are given in combination with currently approved cancer medications

Energy losses of fast heavy-ion projectiles in dense hydrogen plasmas

It has been recently shown that the Bethe-Larkin formula for the energy losses of fast heavy-ion projectiles in dense hydrogen plasmas is corrected by the electron-ion correlations [Phys. Rev. Lett. \textbf{101}, 075002 (2008)]. We report numerical estimates of this correction based on the values of $g_{ei}(0)$ obtained by numerical simulations in [Phys. Rev. E \textbf{61}, 3470 (2000)]. We also extend this result to the case of projectiles with dicluster charge distribution. We show that the experimental visibility of the electron-ion correlation correction is enhanced in the case of dicluster projectiles with randomly orientated charge centers. Although we consider here the hydrogen plasmas to make the effect physically more clear, the generalization to multispecies plasmas is straightforward.Comment: 5 pages, 1 figure. International Conference on Strongly Coupled Coulomb Systems 2008, Camerino (Italy). To appear in J. Phys.

Quantum critical fluctuations in disordered d-wave superconductors

Quasiparticles in the cuprates appear to be subject to anomalously strong inelastic damping mechanisms. To explain the phenomenon, Sachdev and collaborators recently proposed to couple the system to a critically fluctuating order parameter mode of either id_{xy}- or is-symmetry. Motivated by the observation that the energies relevant for the dynamics of this mode are comparable to the scattering rate induced by even moderate impurity concentrations, we here generalize the approach to the presence of static disorder. In the id-case, we find that the coupling to disorder renders the order parameter dynamics diffusive but otherwise leaves much of the phenomenology observed in the clean case intact. In contrast, the interplay of impurity scattering and order parameter fluctuations of is-symmetry entails the formation of a secondary superconductor transition, with a critical temperature exponentially sensitive to the disorder concentration.Comment: 4 pages, 2 figures include

Carotenoid triplet state formation in Rhodobacter sphaeroides R-26 reaction centers exchanged with modified bacteriochlorophyll pigments and reconstituted with spheroidene

Triplet state electron paramagnetic resonance (EPR) experiments have been carried out at X-band on Rb. sphaeroides R-26 reaction centers that have been reconstituted with the carotenoid, spheroidene, and exchanged with 132-OH-Zn-bacteriochlorophyll a and [3-vinyl]-132-OH-bacteriochlorophyll a at the monomeric, lsquoaccessoryrsquo bacteriochlorophyll sites BA,B or with pheophytin a at the bacteriopheophytin sites HA,B. The primary donor and carotenoid triplet state EPR signals in the temperature range 95–150 K are compared and contrasted with those from native Rb. sphaeroides wild type and Rb. sphaeroides R-26 reaction centers reconstituted with spheroidene. The temperature dependencies of the EPR signals are strikingly different for the various samples. The data prove that triplet energy transfer from the primary donor to the carotenoid is mediated by the monomeric, BChlB molecule. Furthermore, the data show that triplet energy transfer from the primary donor to the carotenoid is an activated process, the efficiency of which correlates with the estimated triplet state energies of the modified pigments